With the goal of reducing the age-associated vasomotor symptoms and decreasing the risk of cardiovascular disease, many women choose over the counter phytoestrogens in favor of estrogens prescribed by their physicians. Genistein is the best studied and most common of the soy-derived phytoestrogens. Genistein is structurally similar to 172-estradiol and has high affinity for the ER2 receptor present in the human vasculature, but low affinity for the ER1 receptor present in reproductive organs. Studies support beneficial effects of soy-derived phytoestrogens on vascular reactivity and endothelial function. However, during genistein treatment the expected improvement in endothelial dependent dilation is attenuated in individuals with insulin resistance. This project is designed to study the impact of genistein on microvascular reactivity both in healthy women and in women with insulin resistance. Our general hypothesis is that genistein improves endothelial function through a nitric oxide mechanism in healthy women, but that this mechanism is ineffective in women with insulin resistance. We will use the cutaneous vasculature as a model to study endothelial function, and will infuse estradiol and genistein directly into the skin using microdialysis while measuring microvascular blood flow with laser Doppler flowmetry. Our first Aim will use dose-response curves to determine the 172-estradiol and genistein effects on the peripheral microvasculature in women with and without insulin resistance. We hypothesize that both hormone infusions will increase blood flow in both groups of women, but the vasodilation will be attenuated in women with insulin resistance. Our second Aim tests the hypothesis that nitric oxide mediates the estradiol and genistein-induced vasodilation in healthy women, but is not a factor in the more moderate vasodilation seen in women with insulin resistance. Women take genistein and other phytoestrogens assuming a level of cardiovascular protection, but data have not definitively demonstrated these benefits. Our studies will directly assess the extent to which genistein impacts vasodilation and examine the mechanism for its effects. Moreover, our findings will provide a basis to study the impact of genistein and other phytoestrogens on other conditions associated with compromised peripheral circulation such as Reynaud's disease and hypertension. The proposed studies will not only provide mechanistic information on the interaction between estradiol, genistein, insulin resistance and endothelial function, but will serve as a basis for future studies in older women and men with insulin resistance.